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TitleA dual mechanism of action of AT-527 against SARS-CoV-2 polymerase.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 621, Year 2022
Publish dateFeb 2, 2022
AuthorsAshleigh Shannon / Véronique Fattorini / Bhawna Sama / Barbara Selisko / Mikael Feracci / Camille Falcou / Pierre Gauffre / Priscila El Kazzi / Adrien Delpal / Etienne Decroly / Karine Alvarez / Cécilia Eydoux / Jean-Claude Guillemot / Adel Moussa / Steven S Good / Paolo La Colla / Kai Lin / Jean-Pierre Sommadossi / Yingxiao Zhu / Xiaodong Yan / Hui Shi / François Ferron / Bruno Canard /
PubMed AbstractThe guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the ...The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, AT-527 is converted into its triphosphate form, AT-9010, that presumably targets the viral RNA-dependent RNA polymerase (RdRp, nsp12), for incorporation into viral RNA. Here we report a 2.98 Å cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-nsp8-RNA complex, showing AT-9010 bound at three sites of nsp12. In the RdRp active-site, one AT-9010 is incorporated at the 3' end of the RNA product strand. Its modified ribose group (2'-fluoro, 2'-methyl) prevents correct alignment of the incoming NTP, in this case a second AT-9010, causing immediate termination of RNA synthesis. The third AT-9010 is bound to the N-terminal domain of nsp12 - known as the NiRAN. In contrast to native NTPs, AT-9010 is in a flipped orientation in the active-site, with its guanine base unexpectedly occupying a previously unnoticed cavity. AT-9010 outcompetes all native nucleotides for NiRAN binding, inhibiting its nucleotidyltransferase activity. The dual mechanism of action of AT-527 at both RdRp and NiRAN active sites represents a promising research avenue against COVID-19.
External linksNat Commun / PubMed:35110538 / PubMed Central
MethodsEM (single particle)
Resolution2.98 Å
Structure data

31061

7ed5

EMDB-31061, PDB-7ed5:
A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
Method: EM (single particle) / Resolution: 2.98 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-AT9:
[[(2R,3R,4R,5R)-5-(2-azanyl-6-oxidanylidene-1H-purin-9-yl)-4-fluoranyl-4-methyl-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate

Source
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
KeywordsVIRAL PROTEIN / SARS-CoV-2 / nsp12 / NiRAN / RdRp / AT-9010 / AT-527

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